The cellular metabolism is essential to generate resources such as ATP and biomass for their growth. The metabolic pathway to generate ATP is glycolysis and OXPHOS in mitochondria. Normal cells generate ATP via OXPHOS in mitochondria since 38 ATP molecules are generated per glucose molecule. However fast growing cells use glycolysis to generate ATP and lactate is the final metabolite in the process. For a long time, the dependency on OXPHOS is thought to be determined by availability of oxygen because oxygen is the molecule that accepts electrons during OXPHOS. Recently, the studies have shown that oxygen is not the determinant for OXPHOS, but rather cellular demands for biomass and NADH/NADPH in fast growing cells actively choose to use glycolysis rather than OXPHOS. Cancer cells are the best example of transformed metabolism and uncontrolled proliferation. Dr. Otto Warburg in 1920s noticed the cancer cells mainly use glycolysis and produce high level of lactate. The highly glycolytic nature of cancer metabolism is currently named “Warburg effect”. The glycolytic metabolic feature leads to a speculation that cancer cells might have dysfunctional mitochondria. Recent studies however showed the significance of OXPHOS in cancer cells, in particular, cancer stem cell-like population, migrating cancer cells, circulating cancer cells in metastasis.
Metformin is a biguanide used for the treatment of diabetes. It is known to be an OXPHOS inhibitor that has been clinically used for a long time. Several retrospective epidemiology studies pointed out that cancer incidence was lower in diabetic patients who were treated with metformin. The anticancer effect of metformin has been demonstrated in in vitro and in vivo models of breast, colon, prostate and lung cancer. The efficacy of metformin is limited by its weak potency and distribution due to the cationic property, therefore the dependency on Organic Cation Transporter 1 (OCT1) in order to enter cells. Many studies used a more potent biguanide and antidiabetic drug, phenformin to demonstrate the anticancer effect of OXPHOS inhibitor. Phenformin is more lipophilic than metformin and shows less dependency on OCT1 to enter cells. Several studies showed phenformin has activity of tumor growth inhibition and moreover prevent rising of cells resistant to targeted therapies (YuanP, Proc Natl Acad Sci. 2013, 110(45): pp 18226-18231). Phenformin was shown to inhibit the growth of slow growing cancer cells or JARID1Bhigh cells that might be responsible for drug resistance and relapse of disease (RoeschA, Cancer Cell, 2013, 23(6), pp 811-825)
In the last decade, the main anticancer therapy was focused on development of inhibitors of oncogenes or signaling proteins such as kinases and growth factor receptors. The response rates were marginal in most cases. The initial responses by the best therapies apparently looked promising, but majority of patients relapsed with much more aggressive and drug resistant form of cancers. The true mechanism of relapse is still needed to be discovered, but multiple relapse mechanism have been reported such as secondary mutations on the same target or activation of different route of signaling pathway. The mechanism of phenformin in overcoming drug resistance is not still clear. The OXPHOS inhibition may prevent further reprogramming after reprogramming upon co-treatment with targeted therapy, therefore it may cause energy crisis or prevent growth of slow growing population depending on OXPHOS.
Metformin has limited efficacy and tissue distribution and phenformin has been withdrawn from the market due to fatal safety issues. Thus, the conventional biguanide used for diabetic treatment have limitations as an anticancer agent.